Targeting Nrf2/HO-1, NF-κB, and Apoptotic Pathways: Mechanistic Evaluation of Phlorizin Nanoparticles in Diabetic Renal Injury.

Diabetes mellitus (DM) is a chronic metabolic disorder associated with hyperglycemia, dyslipidemia, oxidative stress, inflammation, apoptosis, and renal dysfunction. Although phlorizin (PHL) possesses well-documented antidiabetic properties, its clinical applicability is limited by poor bioavailability and rapid metabolism, which may restrict its therapeutic efficacy. This study evaluated the therapeutic potential of phlorizin (PHL) and its chitosan nanoparticle formulation (PHL-CSNPs) in streptozotocin (STZ)-induced type 1 diabetic rats. Ninety adult male albino rats were randomly divided into six groups (n = 15 each): non-diabetic control, non-diabetic treated with crude PHL, non-diabetic treated with PHL-CSNPs, diabetic untreated (STZ-induced T1DM), diabetic treated with crude PHL, and diabetic treated with PHL-CSNPs. STZ-induced T1DM caused significant reductions in serum insulin, body weight gain, renal antioxidant defences, and mitochondrial function, accompanied by marked elevations in fasting blood glucose, dyslipidemia, oxidative stress markers, pro-inflammatory cytokines, apoptotic markers, and renal fibrotic mediators, as well as pronounced histopathological and ultrastructural kidney damage. In diabetic rats, treatment with PHL-CSNPs significantly improved insulin levels, glucose homeostasis, and body weight, restored lipid profiles and antioxidant enzyme activities, enhanced mitochondrial respiratory complex activities and ATP production, suppressed NF-κB-mediated inflammation, upregulated Nrf2/HO-1 signalling, decreased Bax and caspase-3 levels, increased Bcl-2 levels, and reduced TGF-β1-mediated fibrosis. Crude PHL provided moderate protective effects but was consistently less effective than the nanoparticle formulation. Importantly, the chitosan nanoparticle formulation markedly enhanced the therapeutic efficacy of PHL, likely by improving its stability, bioavailability, and renal tissue delivery, thereby producing stronger antioxidant, anti-inflammatory, and anti-apoptotic effects than crude PHL. Non-diabetic rats treated with either PHL or PHL-CSNPs maintained normal metabolic and renal parameters, confirming the safety of the treatments. Histopathological and ultrastructural analyses further confirmed the preservation of renal architecture in PHL-CSNP-treated diabetic rats. Collectively, this study demonstrates that nanoencapsulation significantly potentiates the biological activity of PHL, providing a clear therapeutic advantage over the crude compound. Overall, these findings demonstrate that PHL-CSNPs provide superior nephroprotective, antioxidant, anti-inflammatory, and metabolic benefits, highlighting their potential as a promising therapeutic strategy for managing type 1 diabetes-induced metabolic and renal complications.